Devices and methods for novel retinal irradiance distribution modification to improve and restore vision without producing corneal vitrification

ABSTRACT

Devices and methods for novel retinal irradiance distribution modification (IDM) to improve, stabilize or restore vision are described herein. Also encompassed herein are devices and methods to reduce vision loss from diseases, injuries and disorders that involve damaged and/or dysfunctional and/or sensorily deprived retinal cells. Conditions that may be treated using devices and methods described herein include macular degeneration, diabetic retinopathy and glaucoma. Therapy provided by retinal IDM devices and methods described herein may also be used in combination with other therapies including, but not limited to, pharmacological, retinal laser, gene and stem cell therapies.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of, and claims the benefit ofpriority to, U.S. application Ser. No. 16/593,269, which is a divisionalof, and claims the benefit of priority to, U.S. application Ser. No.15/693,208, filed Aug. 31, 2017. The disclosures of these applicationsare expressly incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to devices and methods for novel retinalirradiance distribution modification (IDM) to improve, stabilize orrestore vision. The present invention also relates to devices andmethods to reduce vision loss from diseases, injuries and disorders thatinvolve damaged and/or dysfunctional and/or sensorily deprived retinalcells. The applications of the present invention include, but are notlimited to, treatment of macular degeneration, diabetic retinopathy andglaucoma. The therapy provided by retinal IDM devices and methods of thepresent invention can also be used in combination with other therapiesincluding, but not limited to, pharmacological, retinal laser, gene andstem cell therapies.

BACKGROUND

Conventional devices and methods offer suboptimal solutions forimproving vision and/or restoring vision to reduce vision loss fromdiseases, injuries and disorders that involve damaged and/ordysfunctional and/or sensorily deprived retinal cells. Vision loss iscaused by diseases, injuries and disorders including, but not limitedto, age-related macular degeneration (AMD), Stargardt disease, Bestvitelliform macular dystrophy, light-induced retinal injuries, conedystrophies, reverse retinitis pigmentosa, myopic macular degeneration,macular scars, diabetic retinopathy (DR), macular edema, macular hole,macular detachment, macular pucker, vascular retinal disorders(including but not limited to retinal vein occlusions and Coats'Disease), retinitis pigmentosa, glaucoma or other neuroretinal organglion cell disorders and amblyopia (caused by refractive error,medial opacity or obstruction, or an oculomotor condition, or anycombination thereof). AMD, DR and other retinal diseases and disordersare major causes of worldwide vision impairment, including blindness.There are great unmet needs for solutions that provide meaningful visionand vision-related quality of life improvements to patients who sufferfrom vision loss caused by retinal problems. Conventional devices andmethods only offer suboptimal amelioration of, or compensation for, somesymptoms of vision loss from such diseases, injuries and disorders.

Conventional devices and methods for amelioration of, or compensationfor, symptoms of vision loss, such as telescopes (handheld, inelectronic devices, in spectacles, in contact lenses, in intraocularlenses, or in the cornea) or annular multifocal corneal lasertreatments, only magnify images within a small area of view. Devices andmethods for amelioration of, or compensation for, symptoms of visionloss using prisms or prismatic effects (in spectacles, in contactlenses, or in intraocular lenses) only deviate images from objectswithin the visual field angularly onto a small area of the retina. Thehandheld and electronic telescopes require patients to remain stationaryand these telescopes magnify a very small area of the patient's visualfield. Telescopes in spectacles, contact lenses and intraocular devicesrequire visual training over periods of weeks to months, produce tunnelvision, prevent binocular vision, and result in poor ambulatory vision.Telescopes or prisms in intraocular devices involve surgery with risksof severe intraoperative and postoperative complications and adverseevents. Oculomotor training for eccentric fixation requires trainingover a period of weeks to months with diminishing effects over time andabnormal head positioning, with minimal improvements in reading speedand with minimal or no improvements in visual acuity. Prisms in glasses,contact lenses or intraocular lenses are poorly tolerated and can causedouble vision. All optical devices on glasses or contact lenses fail tomaintain a constant moment-to-moment visual correction as the eyes move,preventing the full effects of neural adaptation to develop. Retinalprostheses, such as eyeglass-mounted cameras that transmit wirelessly toa microelectrode array implanted intraocularly within or on a patient'sretina cannot provide high resolution vision and provide only vaguemotion detection and shape discernment. Intraocular implants withtelescopes, prisms, or microelectrode arrays involve surgery with risksof severe intraoperative and postoperative complications and adverseevents, including death, loss of the eye, and complete loss of sight.

Conventional vision aids provide amelioration of, or compensation for,symptoms of visual loss but do not provide restorative benefitsincluding, but not limited to, repair of damaged retinal cells orimprovement of functioning of retinal cells.

Conventional drug therapies including, but not limited to, anti-vascularendothelial growth factor (anti-VEGF) agents for neovascular AMD,diabetic macular edema, and other neovascular retinal disorders and theprostaglandin analogs for glaucoma prevent further progression of visionloss but do not provide significant vision restoration for mostpatients. Conventional device therapies including, but not limited to,retinal laser photocoagulation, photodynamic laser therapy, radiationtherapy, photobiomodulation, subthreshold micropulse laser therapy,glaucoma laser therapy and glaucoma surgery with or without shuntimplantation do not improve vision significantly. Patients who sufferfrom dry AMD, marked by retinal dysfunction with drusen formation andeventual retinal atrophy, have no effective treatment options other thanlifestyle modification, the use of glasses to block ultraviolet or bluelight over the entire visual field, and the use of vitamins and othersupplements.

SUMMARY OF THE INVENTION

The invention described herein includes IDM devices and methods tooptically modify permanently, temporarily or with variable modificationsover time in at least three retinal regions, including a retinalfixation region, spatial, temporal, spatiotemporal, chromatic,achromatic and contrast information distributions of environmental lightfrom an ocular field of view by means of simultaneous light redirectionsfrom a retinal fixation region to at least two other spatially separatedretinal regions (hereinafter: “IDM devices and methods”). The devicesand methods of the invention described herein produce novel retinalirradiance distribution modifications (IDMs) to improve vision. Theinvention described herein also provides vision improvements, visionstabilization and/or vision restoration benefits to patients who havevisual symptoms from, or have suffered visual loss from, diseases,injuries and disorders including, but not limited to, eyes with damagedand/or dysfunctional and/or sensorily deprived retinal cells. Theinvention described herein includes, but is not limited to, retinal IDMdevices and methods for vision improvement and/or vision restoration toovercome vision loss caused by diseases, injuries and disordersincluding, but not limited to, age-related macular degeneration (AMD),Stargardt disease, Best's vitelliform macular dystrophy, light-inducedretinal injuries, cone dystrophies, reverse retinitis pigmentosa, myopicmacular degeneration, macular scars, diabetic retinopathy (DR), macularedema, macular hole, macular detachment, macular pucker, vascularretinal disorders (including but not limited to retinal vein occlusionsand Coats' Disease), retinitis pigmentosa, nutritional retinaldisorders, glaucoma or other neuroretinal or ganglion cell disorders andamblyopia (caused by refractive error, medial opacity or obstruction, oran oculomotor condition, or any combination thereof). In contrast toconventional devices and methods, the retinal IDM invention provides,without requiring oculomotor or perceptual training, better visionand/or quality of life outcomes, fewer and less severe complications oradverse effects, and greater patient convenience and comfort to patientstreated with retinal IDM.

Embodiments of retinal IDM devices described herein include, but are notlimited to, retinal IDM devices to produce cornea photovitrification(CPV); retinal IDM lasers and other light emitting sources to producephotoablation, photodisruption, photoionization, photochemical and/orphotothermal keratoplasty; retinal IDM corneal crosslinking devices;retinal IDM radiofrequency transmitting devices; retinal IDM contactlenses; retinal IDM spectacles; retinal IDM corneal inlays; and retinalIDM intraocular lenses, all of which are configured to produce retinalIDM for vision improvement, with or without vision restorative benefitsincluding, but not limited to, retinal cell repair and/or retinalregeneration.

In some embodiments of the present invention, retinal IDM devices andmethods are combined with non-retinal IDM therapies including, but notlimited to, pharmacological agents, including but not limited to,vascular endothelial growth factor antagonists, retinal laser, ionizingradiation, photobiomodulation, stem cell, genetic, epigenetic andoptogenetic therapies.

While the description herein shows, describes, and points out novelfeatures as applied to various embodiments, it will be understood thatvarious omissions, substitutions, and changes in the form and details ofthe device or method illustrated can be made without departing from thespirit of the disclosure. As will be recognized, certain embodiments ofthe inventions described herein can be embodied within a form that doesnot provide all of the features and benefits set forth herein, as somefeatures can be used or practiced separately from others. All changeswhich come within the meaning and range of equivalency of the claims areto be embraced within their scope.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a cutaway drawing of an eye showing principal ocularstructures.

FIG. 2 is a drawing of an eye in the vicinity of the macula showingretinal structures and dimensions.

FIG. 3 is a schematic retinal microstructure and vision transductiondrawing.

FIG. 4 is a schematic simplified visual pathways drawing.

FIG. 5 is a schematic retina drawing showing the fovea (right circle),optic disc (left circle) and retinal vessels (wavy lines extending tothe optic disc).

FIG. 6 is a graph of visual acuity vs. retinal eccentricity using thefoveolar center as the zero-eccentricity reference.

FIG. 7 is a schematic eye drawing with two light rays incident on theparacentral cornea at points 1 and 2.

FIG. 8 is a schematic retina drawing showing the fovea A with a centraldysfunctional retinal area B.

FIG. 9 is a schematic retina drawing showing a four-quadrant retinalirradiance distribution from a central area into quadrants I through IV.

FIG. 10 is a schematic retina drawing showing the fovea A withnon-central dysfunctional retinal areas B, C and D and a candidatefunctional retinal area E into which retinal IDM can increase retinalirradiance by directing irradiance away from B, C and D.

FIG. 11A is a corneal map showing local radii of curvature produced byCPV IDM treatment. FIG. 11B shows an enlarged central area of FIG. 11A.

FIG. 12 shows a schematic corneal anterior surface radius of curvature(ROC) profile for retinal IDM.

FIG. 13 shows an ETDRS visual acuity chart with lines labelled in logMAR(left) and Snellen (right) units. Each line on the chart has fiveletters; changes in visual acuity are often given in terms of theletters gained or lost.

FIG. 14 shows measurements of best spectacle-corrected distance visualacuity (CDVA) vs. time for right (OD) and left (OS) eyes of Patient A.The ordinate grid is shown in both logMAR and Snellen units. Theabscissa grid is shown in 3 month increments.

FIG. 15 shows measurements of best spectacle-corrected near visualacuity (CNVA) vs. time for right (D) and left (OS) eyes of Patient A.The ordinate grid is shown in both logMAR and Snellen units. Theabscissa grid is shown in 3 month increments.

FIG. 16 shows the vision-related quality of life VFQ-25 composite scorefor Patient A pre- and post-CPV IDM treatment.

FIG. 17 shows VFQ-25 vision scores for Patient A pre- and post-CPV IDMtreatment.

FIG. 18 shows VFQ-25 psychosocial scores for Patient A pre- and post-CPVIDM treatment.

FIG. 19 shows retinal sensitivity measures for Patient A pre- andpost-CPV IDM treatment.

FIG. 20 shows measurements of best spectacle-corrected distance visualacuity (CDVA) vs. time for right (OD) and left (OS) eyes of Patient B.The ordinate grid is shown in both logMAR and Snellen units. Theabscissa grid is shown in 3 month increments.

FIG. 21 shows measurements of best spectacle-corrected near visualacuity (CNVA) vs. time for right (D) and left (OS) eyes of Patient B.The ordinate grid is shown in both logMAR and Snellen units. Theabscissa grid is shown in 3 month increments.

FIG. 22 shows the vision-related quality of life VFQ-25 composite scorefor Patient B pre- and post-CPV IDM treatment.

FIG. 23 shows VFQ-25 vision scores for Patient B pre- and post-CPV IDMtreatment.

FIG. 24 shows VFQ-25 psychosocial scores for Patient B pre- and post-CPVIDM treatment.

FIG. 25 shows cross-sections through schematic retinal irradiancedistributions.

FIG. 26 shows a cross-section of a cornea that has received femtosecondlaser treatments to produce corneal anterior surface radius of curvature(ROC) changes for retinal DM.

FIG. 27 is an IDM intraocular lens drawing with modifications inparacentral areas.

FIG. 28 is an IDM intraocular lens drawing with two prismatic sectors.

FIG. 29 is a schematic cross-section of an IDM contact lens withparacentral steepened regions.

FIG. 30 is a schematic cross-section of an IDM corneal inlay implantedwithin a cornea.

DETAILED DESCRIPTION OF THE INVENTION

The retinal irradiance distribution modification (IDM) inventiondescribed herein includes retinal IDM devices and methods that opticallymodify permanently, temporarily or with variable modifications over timein at least three retinal regions, including a retinal fixation region,spatial, temporal, spatiotemporal, chromatic, achromatic and contrastinformation distributions of environmental light from an ocular field ofview by means of simultaneous light redirections from a retinal fixationregion to at least two other spatially separated retinal regions(hereinafter: “IDM”). Retinal IDM devices and methods have applicationsfor vision improvement or stabilization and/or vision restoration and/oramelioration of and/or compensation for visual symptoms from ophthalmicconditions, diseases, injuries and disorders, including, but not limitedto, in eyes with visual loss due to diseases, injuries and disordersthat involve damaged and/or dysfunctional and/or sensorily deprivedretinal cells. The IDM devices and methods reduce visual loss caused bydiseases, injuries and disorders including, but not limited to,age-related macular degeneration (AMD), Stargardt disease, Bestvitelliform macular dystrophy, light-induced retinal injuries, conedystrophies, reverse retinitis pigmentosa, myopic macular degeneration,macular scars, diabetic retinopathy (DR), macular edema, macular hole,macular detachment, macular pucker, vascular retinal disorders(including but not limited to retinal vein occlusions and Coats'Disease), retinitis pigmentosa, nutritional retinal disorders, glaucomaor other neuroretinal or ganglion cell disorders and amblyopia (causedby refractive error, medial opacity or obstruction, or an oculomotorcondition, or any combination thereof).

Vision processing involves the interaction of the two eyes and the brainthrough a network of neurons, receptors, and other specialized cells.The first steps in this sensory process include the stimulation of lightreceptors in the retina, conversion of the light stimuli into neuralsignals, processing of these neural signals through many kinds ofretinal interneurons, and transmission of electrical signals containingspatial, temporal, spatiotemporal and chromatic visual information fromeach eye to the brain. Processing by retinal interneurons involveschemical and electrical messages sent among retinal cell types includingthe feedforward pathway from photoreceptors to bipolar cells and on toganglion cells, along with interactions of these cell types with andamong horizontal and amacrine cells. This information is furtherprocessed in the brain. Functional vision results when the brainintegrates retinal information across space, time, and saccades.

Retinal irradiance is the amount of light power per unit area that isincident on the retina. Irradiance is measured in units of W/m² where Wis the light power in watts and m is a meter of length. An eye with aretinal disorder can have decreased retinal sensitivities of varyingmagnitudes to light irradiance in retinal regions. Decreased retinalsensitivities can be demonstrated by diagnostic testing, including, butnot limited to, microperimetry. There is incorrect and/or impartialvisual processing of light rays within the environmental field of viewof a retinal region with decreased retinal sensitivities. Followingretinal IDM treatment by retinal IDM devices and methods of theinvention described herein, the distribution of visual information inthe environmental field of view of an eye is modified by multiple andspatially separated redirections of the light rays onto multiple retinalregions, including regions with better retinal sensitivities. RetinalIDM, therefore, is distinct from a modification of the total irradianceonto the entire retina and may or may not include a modification of thetotal irradiance onto the entire retina. Retinal spectral irradiance isthe amount of light power per unit area per unit wavelength that isincident on the retina. Detection of light by the retina is differentfor different wavelengths of light and for photopic, mesopic andscotopic illumination conditions. IDM devices and methods are useful inall illumination conditions including, but not limited to, day visionand night vision illumination conditions. Unless otherwise noted in thisapplication, retinal irradiance is always considered for visible lightwith a spectral distribution including, but not limited to, sunlight orlight with a color rendering index (CRI) similar to sunlight (i.e.,CRI≥80, with a maximum of 100—a perfect match of the spectraldistribution to sunlight) and for photopic illumination conditionsincluding, but not limited to, daylight.

It is understood that retinal irradiance and retinal irradiancedistribution can be measured for both model and ex vivo eyes by usingphotometric instrumentation known to one skilled in the art including,but not limited to, photodiode arrays, charge-coupled device (CCD)sensors and complementary metal oxide semiconductor (CMOS) sensors. Itis also understood to one skilled in the art that retinal irradiance andretinal irradiance distribution can be predicted using raytracingcomputations with model eyes.

The retinal irradiance distribution, together with its spatiotemporal,chromatic, achromatic and contrast information, can be specified onvarious spatial and temporal scales. Spatial scales include, but are notlimited to: A) receptive fields of domains of retinal cells including,but not limited to, spatial scales as small as an individualphotoreceptor and including both the center and surround of each cell'sreceptive field; B) the entire fovea; C) the entire macula; D) theentire central visual field that extends to an eccentricity of ca. 20°;and E) the entire visual field. Locations on the retina with respect tothe center of the foveola can be specified in terms of polar coordinatesr,θ or r′,θ in which r is the distance in mm units or r′ is the distancein terms of retinal eccentricity in units of degrees, and θ is theangular coordinate.

Temporal scales include, but are not limited to: A) a moment-to-momenttimescale that can be as short as 10 milliseconds, during whichirradiance and contrast can be modified from: i) changes in the radianceof objects in visual space, ii) from movements of the eye, includingboth fixational movements and saccades that cause light (from differentobjects in the visual space) to irradiate a spatial region of theretina, or iii) any combination of i and ii; B) an intermediatetimescale, that extends to several minutes duration, during whichprocesses of retinal adaptation occur; C) a long timescale, that is inthe range of days to years duration, during which the overall irradianceon a spatial region of the retina can affect the health of retinalcells; and D) a second long timescale that be in the range of days toyears duration, during which processes of neural adaptation occur.

Contrast refers to changes in irradiance across the spatial and temporalscales described above. Contrast can also refer to changes in irradianceon temporal scales that match the dynamics of the light responses inretinal cells. Contrast can also refer to changes in irradiance onspatio-temporal scales that match the dynamics of motion-sensitive cellsin the retina. Contrast can also refer to changes in spectral irradiancethat match the chromatic sensitivities of retinal cells.

The retina of the eye is illustrated on the cutaway drawing of an eyeshown in FIG. 1 . Principal ocular structures are the cornea, the iris(defining the pupil aperture), the lens and the retina including thefovea, macula, optic disc and blood vessels. The region of the retina inthe vicinity of the macula is shown in FIG. 2 , with identification ofthe fovea and other retinal areas together with their dimensions. Aretinal schematic microstructure and vision transduction drawing isshown in FIG. 3 , in which light produced by IDM devices and methodsirradiates the retinal, producing electrical signals from photoreceptor(cone and rod) cells; these electrical signals are pre-processed byspecialized retinal (horizontal, bipolar, amacrine and ganglion) cellsleading to action potentials (electrical “spikes”) that propagatethrough the optic nerve (and ultimately to the visual cortex) throughaxons (nerve fibers) emanating from retinal ganglion cells. The choroidcontains capillary blood vessels that provide nutrients to retinal cellsand that transport waste products from the retina.

FIG. 4 shows schematic simplified pathways for the cortical processingof visual information. Retinal ganglion cell axons connect to thelateral geniculate nucleus (LGN) as well as to other subcorticalstructures including, but not limited to, the superior colliculus thatare not shown. LGN relay cells connect to the primary visual cortex(area V1). The primary visual cortex in turn connects to multiplecortical visual areas (including, but not limited to, the ventral streamand the dorsal stream) that process information to provide visualoutcomes including, but not limited to, spatial vision, motionperception, depth perception, form perception and color vision. Thevisual cortex interacts with the thalamus via recurrent loops to produceintegrated visual perception. Visual cortical areas also interact withsubcortical structures including, but not limited to, the basal ganglia,thalamus, cerebellum, superior colliculus and brainstem to control eyemovements. Subcortical visual processing includes, but is not limitedto, eye and head movements, pupil sizes and circadian rhythm. It isunderstood that vision improvement including, but not limited to,neuroadaptation involves the complex interaction of neural processingbetween and among all the stages of the visual pathway.

A schematic retina drawing is shown in FIG. 5 . The fovea is shown asthe circle at the right in FIG. 5 with 0°-180° (temporal-nasal) and90°-270° (superior-inferior) meridians dividing the retinal area intofour quadrants: I (superior-temporal), II (superior-nasal), III(inferior-nasal) and IV (inferior-temporal). Foveal polar coordinatesr,θ specify locations on the retina referenced to the foveolar center“X”. The fovea is approximately 0.75 mm (2.5° eccentricity) in radius;it contains the highest density of photoreceptors (cones) for thehighest spatial resolution of vision. The optic disc is shown as thecircle at the left in FIG. 3 with retinal blood vessels represented aswavy lines.

FIG. 6 shows the variation of visual acuity (both in logMAR and Snellenunits) as a function of retinal eccentricity. FIG. 6 is redrawn fromFIG. 3 of Williams D R and Coletta N J, Cone spacing and the visualresolution limit, J Am Opt Soc A (1987). Measurements are for twosubjects (circle and square symbols); a mean value of 0.907 logMAR(20/162 Snellen) was also measured at 20° retinal eccentricity. Aquadratic fit to the measurements is shown. Conversion from retinaleccentricity: 1° retinal eccentricity=approximately 0.3 mm. The foveaextends to ca. 2.5° retinal eccentricity. The greatest visual acuity isobtained for light focused onto the foveal center of a fully functionalretina. Both defocus and lack of full retinal functionality can reducevisual acuity. Conventional vision aids including, but not limited to,spectacles and contact lenses can improve focus but cannot improveretinal functionality. Although useful vision can be based on usinglarge regions of the retina outside the fovea (i.e., outsideapproximately 2.5° retinal eccentricity)—see FIG. 6 —these regionsoutside the fovea may be underutilized if higher spatial resolutionvisual information from the fovea is weighted preferentially in thevisual cortex.

The retinal irradiance distribution modification (IDM) inventiondescribed herein includes retinal IDM devices and methods that opticallymodify permanently, temporarily or with variable modifications over timein at least three retinal regions, including the fovea or anotherretinal fixation region, spatial, temporal, spatiotemporal, chromatic,achromatic and contrast information distributions of environmental lightfrom an ocular field of view by means of light redirections from thefovea or another retinal fixation region to at least two other spatiallyseparated retinal regions. The retinal regions are defined by ranges ofpolar coordinates, wherein the spatially separated retinal regions arenon-overlapping regions, partly overlapping regions or any combinationof non-overlapping and partly overlapping regions and wherein theamount(s) and location(s) of retinal IDM are for predetermined spatialdistribution(s) with or without predetermined temporal distributions.The retinal irradiance distribution modifications contain informationincluding, but not limited to, spatial, temporal, spatiotemporal,chromatic, achromatic and contrast information or any combinationthereof.

The retinal IDM invention has applications for both vision improvementand vision restoration in diseased eyes as described herein: A—forvision and quality of life improvement and B—for vision restorationbenefits including, but not limited to, retinal cell repair and/orretinal regeneration. It is understood that, in some embodiments, visionimprovement can be obtained by retinal IDM treatment using the retinalIDM devices and methods described herein without vision restorationbenefits, in that some regions of the retina may remain partly orcompletely dysfunctional or may even become less functional as timeelapses after retinal IDM treatment. It is also understood that, in someother embodiments, both vision improvement and beneficial visionrestoration effects, including increased functionality of some regionsof the retina that were partly or completely dysfunctional prior toretinal IDM treatment, can be obtained due to retinal IDM treatment.

In some embodiments of the invention described herein that are intendedfor vision improvement, retinal IDM devices and methods are configuredto optically redirect light from one or more partly or completelydysfunctional retinal areas and to redirect that light, in whole or inpart, onto two or more retinal areas, including one or more functionalretinal areas, wherein the dysfunctional retinal areas include, but arenot limited to, at least one of an area of dysfunctional fovealphotoreceptors, multiple areas of dysfunctional foveal photoreceptors, adysfunctional preferred retinal locus (PRL), multiple dysfunctionalPRLs, multiple spatially separated dysfunctional retinal areas ofphotoreceptors or any combination thereof, wherein the functionalretinal areas include, but are not limited to, at least one of a retinalarea of functional photoreceptors, multiple retinal areas of functionalphotoreceptors, and multiple spatially separated functional retinalareas of photoreceptors wherein all the functional retinal areas ofphotoreceptors have functional signaling to functional ganglion cells.

In some embodiments of the invention described herein, the functionalretinal areas include, but are not limited to, a. at least two spatiallyseparated areas in at least two different quadrants (see FIG. 5 ) and b.at least one spatially separated area in each of the four retinalquadrants (see FIG. 5 ).

The retinal areas are defined by ranges of polar coordinates, whereinthe spatially separated retinal areas are non-overlapping areas, partlyoverlapping areas or any combination of non-overlapping and partlyoverlapping areas, wherein the amount(s) and location(s) of retinal IDMare for predetermined spatial distribution(s) with or withoutpredetermined temporal distribution(s), and wherein the retinalirradiance distribution modifications contain information including, butnot limited to, spatial, temporal, spatiotemporal, chromatic, achromaticand contrast information or any combination thereof.

In some embodiments of the retinal IDM invention described herein, thespatially separated retinal areas include multiple areas in each of thefour retinal quadrants in order to increase the likelihood ofredirecting light: a. onto a functional area or areas in eyes with manydysfunctional areas, b. onto multiple functional areas to be used fordifferent visual tasks, and c. onto multiple functional areas that canbe used if or as the retinal disease progresses.

In some embodiments of the retinal IDM devices and methods of theinvention described herein, the retinal IDM alters the moment-to-momentpatterns of light irradiance coming from edges and objects to increasethe relative irradiance difference on nearby photoreceptors (i.e.,increases the contrast).

In some embodiments of the retinal IDM devices and methods of theinvention described herein, the pattern of retinal irradiancedistribution modification (IDM): (i) improves neural computation withintegration of additional and/or more correctly coded retinalinformation from macular and peripheral retinal cells—including, but notlimited to, photoreceptors, bipolar cells, amacrine cells, horizontalcells, Müller glial cells, ganglion cells or any combination of retinalcells—to enable processing of more complete stimulus patterns and/or(ii) improves functioning of retinal circuitry, including connectivityfunctions in visual processing involving photoreceptors, ganglion cells,amacrine cells, bipolar cells, horizontal cells, and Müller cells or anycombination thereof and/or (iii) triggers processes of neuraladaptation, including but not limited to, use of alternate, latent,and/or new visual pathways in the retina and brain including, but notlimited to: a. rerouting of visual information encoded by peripheralareas of the retina to neurons at high levels of the visual cortex withreceptive fields normally tasked with encoding objects at thecenter-of-gaze, permitting beneficial alteration of crowding propertieswith reduced critical spacing in those peripheral areas and/or b.changing the destination of saccadic eye movements (herein, referred toas a “fixation”) to new retinal loci and/or c. beneficially changing theamplitude and/or speed of eye movements within a fixation and/or d.beneficially changing the interaction of the saccadic corollarydischarge circuit with the rest of the visual cortex and/or e. producingmore effective and spontaneous searching to achieve more effectiveintegration of a greater amount of more correct visual information bysearching mechanisms including, but not limited to, spontaneouslyproducing motor learning in the eye movement strategy to both collectinformation from a greater area of the visual scene and use morefunctional retinal cells for improved visual information.

In some embodiments of the retinal IDM devices and methods of theinvention described herein, retinal IDM re-routes central visualinformation (typically, but not limited to, information at thecenter-of-gaze) through alternative retinal pathways, thereby restoringthe transmission of high-resolution spatial information from these areasof visual space to the rest of the brain—including but not limited tothe cerebral cortex, basal ganglia, thalamus, superior colliculus, andother brainstem nuclei—thereby enhancing global visual processingmechanisms, including, but not limited to: a. enhancing global poolingof contour information and/or b. improving shape discrimination and/orc. improving motion processing and/or d. improving color processingand/or e. improving visually guided behavior or any combination thereof.

In some embodiments of the retinal IDM devices and methods of theinvention described herein, retinal IDM triggers processes of neuraladaptation in central brain circuits (including, but not limited to, thevisual cortex and/or the visual thalamus and/or superior colliculus orany combination thereof), including but not limited to structural andsynaptic plasticity that include, but are not limited to:

a. restoring visual perception to areas of visual space corresponding todamaged areas of the retina, which had, prior to treatment, producedlittle or no visual perception (i.e., were scotomata) by inducingneurons in central brain circuits to develop spatial receptive fieldscovering these previously scotomata; and/orb. reducing and/or eliminating distortions of the visual field in theareas of visual space around the scotomata by incorporating these newspatial receptive fields into local spatial maps and by reorganizingthem into a continuous, undistorted map of visual space (i.e.,counteracting inaccurate perceptual filling-in).

In some embodiments of the retinal IDM devices and methods of theinvention, retinal IDM improvement of visual perception occurs by theformation of new visual pathways from functional areas of the retinathat encode high fidelity information about regions of visual space,which were, prior to treatment, within scotomata. For example, thedistortion of the visual field perceived by patients with maculardegeneration can result from an incorrect remapping of the spatialreceptive fields of neurons in the central brain. In this remapping, thereceptive fields of neurons covering the dysfunctional region of theretina expand and shift to include areas of visual space correspondingto functional regions of the retina. This causes neurons farther away toremap in a similar fashion, and so on. Taken together, these processesinduce a global distortion in the receptive field map, with the clinicalsymptom of straight line objects such as letters, telephone poles andsigns becoming wavy, also known as metamorphopsia. After treatment bysome embodiments of the IDM invention, the newly formed receptive fieldscovering areas of visual space that were, prior to treatment, withinscotomata become incorporated into the spatial map within each visualarea. This incorporation induces a process of reorganization thatreverses the distortion caused by the macular degeneration and therebyrestores a continuous, undistorted map of visual space within eachvisual area. The wavy letters, poles and signs become straight again.

In some embodiments of the retinal IDM devices and methods of theinvention described herein, retinal IDM enables beneficial corticalreorganization including, but not limited to, altered crowdingproperties with smaller critical spacing in the retinal periphery,wherein retinal IDM directs attention to new eccentric preferred loci orother retinal viewing area/s. The altered crowding properties include,but are not limited to, a loss of the radial-tangential anisotropy ofthe crowding zone. Retinal IDM permits, after spontaneous repeated useof the new preferred retinal location (“PRL”) and/or PRLs and/or retinalviewing areas, decreases in the sizes of the crowding zones around thenew PRL or PRLs or retinal viewing areas because of cortical plasticity.The plasticity causes the spatial properties at the PRL/PRLs/retinalviewing areas to become more fovea-like. Both the magnitude and extentof crowding are decreased to the amounts normally found around thefovea. Reduction in the extent of crowding along the major axiscontributes to the less elliptical shape of the crowding zone at thePRL/PRLs/retinal viewing areas, which decreases the detrimental effectsof crowding, thereby improving visual acuity and visual function.

Some embodiments of the retinal IDM devices and methods of the inventiondescribed herein, unlike conventional devices and methods, improvevision by y awakening, without requiring oculomotor or perceptualtraining, residual functional vision pathways, thereby enabling patientsto discover and use the resulting vision immediately or within days orwithin weeks and with additional improvement over months.

In some embodiments of the retinal IDM devices and methods of theinvention described herein, vision improvement is greatly enhanced byhaving a pattern of retinal IDM that is stable across time on amoment-to-moment basis as the eyes move naturally in vision.

Some embodiments of the retinal IDM invention described herein produce,without requiring perceptual or oculomotor training, natural awarenessin a treatment subject of one or more alternate functional visualpathways and natural sensorimotor learning without causing tunnelvision, polyopia or binocular diplopia in a treated subject.

Some embodiments of the retinal IDM devices and methods of the inventiondescribed herein stabilize vision and/or reduce, compared to anuntreated control group, the rate of vision loss and/or improve visionafter a vision loss from a disease, injury or disorder involving retinalcell damage, retinal cell dysfunction, retinal cell sensory deprivationor any combination thereof. The vision improvement includes, but is notlimited to, visual acuity (including both uncorrected and bestspectacle-corrected visual acuity for distance, intermediate and nearvisual acuity), hyperacuity, stereoacuity, vernier acuity, contrastsensitivity, depth of focus, color vision, peripheral vision, nightvision, face recognition, light adaptation, dark adaptation,vision-related quality of life, or any combination thereof.

In some embodiments of the retinal IDM devices and methods of theinvention described herein, retinal IDM enables sustained and/ortransient attention. When spatial covert attention is directed to atarget location, sustained attention enhances sensitivity strictly viacontrast gain, whereas transient attention involves a mixture of bothcontrast gain and response gain.

In some embodiments of the retinal IDM devices and methods of theinvention described herein, retinal IDM improves visual functioning,including, but not limited to, connectivity functions in visualprocessing of retinal tertiary network cells, including, but not limitedto, ganglion cells, amacrine cells, bipolar cells, Müller cells or anycombination thereof.

In some embodiments of the retinal IDM devices and methods of theinvention described herein, retinal IDM improves visual field deficitson perimetry and/or microperimetry examination and/or preferentialhyperacuity perimetry and/or restores electroretinogram (ERG) amplitudesand/or visually evoked potentials.

Some embodiments of the retinal IDM devices and methods of the inventiondescribed herein enable preferred retinal locus or loci relocation tomore functional location or locations on an ongoing basis and fordifferent binocular visual tasks.

Some embodiments of the retinal IDM devices and methods of the inventiondescribed herein, unlike conventional devices and methods: (i) enableunilateral or bilateral treatment of patients with visual loss fromdisorders damaging retinal cells and/or decreasing functioning ofretinal cells and/or sensorily depriving retinal cells and/or (ii)provide rapid vision improvement continuing over months and years withadditional sensory and/or oculomotor neuroadaptation without requiringperceptual or oculomotor control training.

Some embodiments of the retinal IDM devices and methods of the inventiondescribed herein, unlike conventional devices and methods withlife-threatening or sight-threatening complications or adverse events,provide vision improvement after loss from retinal disorders withoutcomplications or adverse events including, but not limited to,clinically significant changes in intraocular pressure, central cornealthickness, corneal endothelial cell density; corneal decompensation,corneal epithelial cell loss, infection or loss of visual functionsincluding, but not limited to, best-corrected distance visual acuity,best-corrected near visual acuity, contrast sensitivity, and stereopsis.

In some embodiments of the invention described herein that are intendedfor vision restoration effects including, but not limited to, retinalcell repair and/or retinal regeneration, retinal IDM devices and methodsare configured to:

-   -   a. decrease by at least 0.1% the retinal irradiance from the        field of view on spatially separated retinal areas, including        partially or completely dysfunctional retinal areas, wherein the        decrease continues over the defined long time scale, and        increase by at least 0.1% the retinal irradiance from the field        of view on spatially separated (other than those in a.) retinal        areas, including more functional retinal areas, wherein the        increase continues over the defined long timescale wherein it is        understood that retinal irradiance and retinal irradiance        distribution can be measured for both model and ex vivo eyes by        using photometric instrumentation known to one skilled in the        art including, but not limited to, photodiode arrays,        charge-coupled device (CCD) sensors and complementary metal        oxide semiconductor (CMOS) sensors.

Some embodiments of the retinal IDM devices and methods of the inventiondescribed herein improve vision, after loss from disorders damagingretinal cells and/or decreasing functioning of retinal cells and/orsensorily depriving retinal cells, with a single and rapid treatmentthat is comfortable and pain-free, does not require medication aftertreatment, and does not require retreatment. By comparison, conventionaldevices and methods have numerous disadvantages and treatment burdensincluding, but not limited to, at least one of the following:inconvenience for patients, requirement that the patient remainstationary for usage, limitation to the use of only one eye or only oneeye at a time, limitation to treatment only in one eye (or, if themethod can be performed in two eyes, only sequential treatment),requirement for a long and/or painful procedure, requirement ofpost-procedure medications, requirement for constant uncomfortable ordifficult insertion, provocation of retinal inflammation, andrequirement for multiple/repeat procedures.

Some embodiments of the devices and methods of the retinal IDM inventiondescribed herein repair and/or restore retinal cells and/or increaseretinal cell functioning and/or decrease progressive damage to retinalcells in addition to significantly improving vision with rapidimprovement of neurocomputation and beneficial neuroadaptationcontinuing long-term (i.e., over a period of time extending from daysthrough years after treatment).

Some embodiments of the devices and methods of the retinal IDM inventiondescribed herein compensate for deterioration of the retina caused byphotoreceptor or other retinal cell damage with or without repair ofretinal cells and/or triggering visual system repair processes,including but not limited to, beneficial modulation of trophic factorsand biological repair processes. Biological repair processes include,but are not limited to, regrowth of photoreceptor outer segments,reprogramming of Müller cells, regeneration of retinal cells, andreduction of drusen volume in subjects with diseased photoreceptors,retinal pigment epithelial cells and/or Bruch's membrane.

Some embodiments of the retinal IDM devices and methods of the inventiondescribed herein repair and/or restore retinal cells and/or increaseretinal cell functioning with fewer adverse effects and more patientconvenience. The devices and methods of the present invention overcomedrawbacks and deficiencies of the prior art, including conventionaldevices and methods for repairing retinal cells or increasing retinalcell function or decreasing progressive retinal cell damage by targetingdifferent mechanisms with the novel retinal IDM to produce bettertreatment outcomes more comfortably and more conveniently with fewersystemic and ocular adverse effects. In some embodiments of theinvention described herein, retinal IDM not only improves vision byaltering neurocomputation and neuroadaptation but also by repairingand/or restoring retinal cells. In some embodiments of the invention,retinal IDM also triggers visual system repair processes, includingbiological repair processes, including, but not limited to, regrowth ofphotoreceptor outer segments, reprogramming of Müller cells,regeneration of retinal cells and reduction of drusen volume, whereinthe retinal IDM

-   -   a. decreases by at least 0.1% retinal irradiance from the field        of view of spatially separated retinal areas within at least one        of a foveal area, another PRL, multiple PRLs, a non-PRL retinal        area, multiple non-PRL retinal areas or any combination thereof,        wherein the decrease continues over the previously defined long        timescale, wherein the reduced retinal irradiance decreases        deleterious processes including, but not limited to,        photo-oxidative stress, metabolic stress or a combination        thereof within viable retinal cells, wherein reduction of such        deleterious processes includes, but is not limited to, sparing        photoreceptors, slowing progression of photoreceptor loss,        decreasing drusen volume or any combination thereof; and    -   b. increases by at least 0.1% retinal irradiance from the field        of view on retinal areas (other than in a.), including on areas        with viable retinal cells, wherein the increase continues over        the previously defined long timescale, wherein the increased        retinal irradiance increases activation by the viable cells of        at least one of cell repair, cell regeneration, or a combination        thereof within at least one of damaged retinal cells or retinal        areas with non-functional cells; and    -   c. redirects spatial, temporal, spatiotemporal, chromatic,        achromatic and contrast information contained in irradiance        distributions from one or more dysfunctional to one or more        functional areas of the retina.

In some embodiments of the invention described herein, retinal IDMimproves retinal sensitivity, wherein the improved retinal sensitivityincludes, but is not limited to, improved sensitivity of viable conephotoreceptors, viable rod photoreceptors, viable ganglion cells,amacrine cells, viable bipolar cells and/or partially or completelyregenerated retinal cells. It is understood that retinal sensitivity canbe measured by one skilled in the art by using diagnosticinstrumentation including, but not limited to, microperimetryinstrumentation. In some embodiments of the invention described herein,retinal IDM produces in a treated eye with a retinal disorder,including, but not limited to, macular degeneration, over a time periodof months or years at least one of the following: a. an increase inretinal sensitivity in a retinal region, b. a decrease in the rate ofretinal sensitivity loss compared to an untreated control group, c. adecrease in the rate of photoreceptor loss compared to an untreatedcontrol group, d. a decrease in the area of photoreceptor loss, e. adecrease in drusen volume, f a regeneration of retinal cells, or g. anycombination thereof.

In some embodiments of the invention described herein, retinal IDMincreases retinal absorption of photons in some retinal areas to improvevisual processing for vision and retinal image quality while decreasingcumulative photoabsorption and photodamage in other retinal areas,including, but not limited to, the foveal area, other fixation areas,other macular areas, peripheral areas and any combination of retinalareas in which cumulative photoabsorption and photodamage should bereduced.

In some embodiments of the invention described herein, retinal IDMselectively decreases light irradiance including, but not limited to, onthe fovea, on other fixation areas (preferred retinal loci), on othermacular areas, on peripheral retinal areas, and on any combination ofretinal areas to selectively decrease oxidative stress and/orphototoxicity to retinal structures including, but not limited to,photoreceptors, retinal pigment epithelial cells, Bruch's membrane andchoriocapillaris and/or selectively decreases cumulative light damage,by decreasing oxidative stress and/or phototoxicity including, but notlimited to, in the fovea, in other fixation area/s (preferred retinalloci), in other macular areas, in peripheral retinal areas, or in anycombination of retinal areas.

In some embodiments of the invention described herein, retinal IDMprovides beneficial effects including, but not limited to, selectiveprevention of photoreceptor loss, selective reduction of the rate ofprogression of photoreceptor loss, and decrease of photoreceptor lossincluding, but not limited to, apoptosis and/or necrosis and/orpyroptosis and/or autophagy.

In some embodiments of the invention described herein, retinal IDMselectively reduces light-induced oxidative stress and reactive oxygenspecies in the retinal areas where irradiance is decreased in order toproduce beneficial effects including, but not limited to, protection ofphotoreceptor DNA, promotion of DNA repair, decrease ofpathophysiological parainflammation, decrease of inflammasomeactivation, decrease of detrimental autophagy, including but not limitedto, chaperone-mediated autophagy (a.k.a. microautophagy), decreaseretinal cellular death via apoptosis, decrease activation ofproinflammatory and proangiogenic pathways, decrease other deleteriousprocesses associated with oxidative stress and its resultant excessivereactive oxygen species.

In some embodiments of the invention described herein, retinal IDMselectively decreases photo-oxidation of the retinoid A2E inphotoreceptor outer segments. In some embodiments of the invention,retinal IDM selectively decreases A2E formation and/or promotes A2Ereduction in photoreceptor outer segments without the adverse ocularevents related to delayed dark adaptation, such as nyctalopia,dyschromatopsia, blurred vision and photophobia, of currentinvestigational drugs that reduce A2E formation.

In some embodiments of the invention described herein, retinal IDMselectively decreases retinal irradiance and/or cumulative retinalirradiance in retinal areas to decrease oxidative phosphorylation inretinal areas to decrease reactive oxygen species, thereby preventingmitochondrial dysfunction and/or reversing mitochondrial dysfunction. Insome embodiments of the invention, retinal IDM reduces metabolic and/oroxidative stress and/or metabolic instability of retinal structuresincluding, but not limited to, retinal cells (including, but not limitedto, photoreceptors, retinal pigment cells, Müller glial cells, andganglion cells) and Bruch's membrane in some retinal areas to producebeneficial effects including, but not limited to, reduction of damage toand/or repair of and/or regeneration of damaged retinal structuresincluding, but not limited to, retinal cells (including, but not limitedto, photoreceptors, retinal pigment cells, Müller glial cells, andganglion cells) and Bruch's membrane in some retinal areas.

In some embodiments of the invention described herein, retinal IDMselectively decreases retinal irradiance and/or cumulative retinalirradiance in some retinal areas and/or decreases oxidative stress toproduce beneficial effects including, but not limited to, harnessingMüller glial cells for photoreceptor cell protection and/or regenerationand/or increasing Müller glial cell transdifferentiation and/ordecreasing Müller glial cell gliosis and/or preventing deleteriousretinal remodeling and/or preserving glutamine synthetase expression inMüller cells and/or enabling the retinal microenvironment around Müllercells to support cone function.

In some embodiments of the retinal IDM invention described herein,retinal IDM selectively decreases retinal irradiance and/or cumulativeretinal irradiance in some retinal areas, thereby causing reduction ofdrusen volume (i.e., the number and/or size of drusen).

In some embodiments of the invention described herein, retinal IDMselectively decreases retinal irradiance and/or cumulative retinalirradiance in some retinal areas to produce beneficial effectsincluding, but not limited to, beneficial modulation of trophic factorsand regeneration and/or rescue of retinal structures including, but notlimited to, retinal cells (including, but not limited to,photoreceptors, retinal pigment epithelial cells, Müller glial cells,and ganglion cells) and Bruch's membrane and the external limitingmembrane.

Embodiments of the invention described herein include retinal IDMdevices and methods based on light sources (including, but not limited,to continuous wave and pulsed lasers, including, but not limited to,lasers for corneal photovitrification, corneal photodisruption,intralenticular photodisruption, corneal photoionization, cornealphotodissociation, corneal photoablation, thermal keratoplasty, andphoto-welding), corneal crosslinking systems, corneal radiofrequencytransmitters, spectacles, contact lenses, corneal inlays, intraocularlenses for insertion in phakic, aphakic or pseudophakic eyes, andcombinations thereof configured to produce retinal irradiancedistribution patterns utilizing designs, materials, and optics forretinal IDM in many areas of the retina or throughout the retina tostabilize vision, improve vision, restore vision or reduce the rate ofvision loss compared to an untreated control group after visual lossfrom disorders that involve damaged and/or dysfunctional and/orsensorily deprived retinal cells; wherein the retinal IDM devices andmethods are configured to optically modify permanently, temporarily orwith variable modifications over time in at least three retinal regions,including the fovea or another retinal fixation region, spatial,temporal, spatiotemporal, chromatic, achromatic and contrast informationdistributions of environmental light from an ocular field of view bymeans of simultaneous light redirections from the fovea or anotherretinal fixation region to at least two other spatially separatedretinal regions, wherein the retinal regions are defined by ranges ofpolar coordinates, wherein the spatially separated retinal regions arenon-overlapping regions, partly overlapping regions or any combinationof non-overlapping and partly overlapping regions and wherein theamount(s) and location(s) of retinal IDM are for predetermined spatialdistribution(s) with or without predetermined temporal distributions andwherein the retinal irradiance distribution modifications containinformation including, but not limited to, spatial, temporal,spatiotemporal, chromatic, achromatic and contrast information or anycombination thereof. In some embodiments of the retinal IDM devices andmethods described herein, the retinal devices produce retinal IDM tosimultaneously and optically redirect light from partly or completelydysfunctional retinal areas and to redirect that light, in whole or inpart, onto one or more functional retinal areas, wherein the retinalirradiance distribution modifications contain information including, butnot limited to, spatial, temporal, spatiotemporal, chromatic, achromaticand contrast information or any combination thereof. In some embodimentsof the retinal IDM devices and methods described herein, the retinaldevices produce retinal IDM wherein the amount and location of retinalIDM is for spatially separated retinal areas, that are non-overlappingareas, partly overlapping areas or any combination of non-overlappingand partly overlapping areas; the amount and location of such retinalIDM is for a predetermined spatial distribution with or without apredetermined temporal distribution; wherein the amount and location ofretinal IDM has a pattern and symmetry distinct from that caused byself-generated image modifications including, but not limited to, i) eyemovements that cause a single translation of the entire visual field onthe retina, ii) lens accommodation that causes a change in the focus ofthe entire visual field on the retina and iii) pupildilation/constriction that causes a rapid brightening/dimming of theentire visual field on the retina, as this prevents the central brainfrom being able to compensate for, and hence partially cancel, theeffects of retinal IDM; wherein retinal IDM, without requiringoculomotor and/or perceptual training, inhibits at least one visualpathway used for fixation and excites at least one alternate functionalvisual pathway for fixation in an eye; wherein retinal IDM, withoutrequiring oculomotor and/or perceptual training, produces awareness in atreatment subject of at least one or multiple alternate functionalvisual pathways; wherein retinal IDM also may produce beneficial effectsincluding, but not limited to, reduction of damage to and/or repair ofand/or regeneration of damaged retinal structures including, but notlimited to, retinal cells (including, but not limited to,photoreceptors, retinal pigment cells, Müller glial cells, and ganglioncells) and Bruch's membrane in some retinal areas; and wherein retinalIDM improves vision after a vision loss from one or more of a disease,injury or disorder involving one or more of retinal cell damage, retinalcell dysfunction, retinal cell sensory deprivation or any combinationthereof, wherein the improved vision is configured to result inimprovement of vision-related outcomes including, but not limited to,visual acuity (including both uncorrected and best spectacle-correctedvisual acuity for distance, intermediate and near visual acuity),hyperacuity, depth of focus, color vision, peripheral vision, contrastsensitivity, stereoacuity, vernier acuity, light adaptation, darkadaptation, vision-related quality of life, or any combination thereof.

Some embodiments of the retinal IDM invention described herein alter thecornea of the eye. In some corneal embodiments, a laser retinal IDMdevice is used to modify radii of curvature (ROCs) of the cornea asschematically shown in FIG. 7 . In the unmodified cornea, rays of lightincident on points 1 and 2 are focused onto the fovea, as shown by solidlines in FIG. 7 . Decreasing the ROCs at points 1 and 2 (not shown inFIG. 7 ) changes the directions of light rays to irradiate locations L1and L2 that are outside the fovea. In FIG. 7 , the modified ROC at point2 is decreased by a greater amount compared to the modified ROC at point1, both of which are decreased relative to the unmodified radius ofcurvature; in this case, the greater decrease in radius of curvature atpoint 2 produces a larger redirection of the light ray to irradiatelocation L2 that is separated by a greater distance from the fovea thanthe light ray that irradiates location L1. The light ray relocations atany points on the cornea can be produced by corneal modificationsincluding, but not limited to, modifications of corneal radii ofcurvature, corneal indices of refraction, corneal diffraction, cornealscattering and any combination of corneal modifications thereof. It isunderstood that the sample light rays shown in FIG. 7 are onlyrepresentative of the entire set of light rays that are mapped fromobject space to image space(s) on the retina. In some embodiments of theinvention described herein, retinal IDM includes light ray relocationsproduced by corneal modifications within two or more corneal regionsincluding, but not limited to, central through paracentral sectorsextending to 7 mm or larger optical zone with alternating steeper andflatter sectors within the full 360° angular range on the cornea.

FIG. 8 is a schematic retina drawing showing the fovea A with a centraldysfunctional area B. In this case, a retinal IDM device including, butnot limited to, a device that modifies the cornea should be designed toredirect light rays, with spatiotemporal, contrast, chromatic andachromatic information, away from the central dysfunctional area B tofunctional retinal areas including, but not limited to, the functionalzone of the fovea outside area B. FIG. 9 is a schematic retina drawingthat illustrates a four-quadrant retinal IDM that may be produced byusing a retinal IDM device for retinal IDM from the centraldysfunctional retinal area into four functional retinal areas.

FIG. 10 shows dysfunctional and functional retinal areas with a varietyof shapes and locations on the retina. It is understood by anyoneskilled in the art that any retinal IDM device should be configured toproduce retinal IDM away from dysfunctional retinal areas (B, C and D inthe example of FIG. 10 ) and onto functional retinal areas; in the caseof FIG. 10 , the functional retinal area E is a candidate area intowhich retinal IDM can be used for vision and visual functionimprovements.

Preferred embodiments of retinal IDM devices and methods used to modifyradii of curvature of the cornea include, but are not limited to,corneal photovitrification (CPV) IDM devices (hereinafter “CPV-IDM”devices) that use a light source to irradiate the cornea in order toproduce photovitrification of at least one volume of corneal stromalmaterial, as described in U.S. Pat. No. 9,526,656 by methods describedin U.S. Pat. No. 9,532,904 both of which are incorporated herein intheir entirety by reference. CPV-IDM treatment produces at least onevolume of corneal stromal material that is modified in structure andproperties from its naturally occurring condition into a non-naturallyoccurring glass-like condition as described in U.S. Pat. No. 9,545,339which is incorporated herein in its entirety by reference. In theinvention described herein, preferred retinal IDM devices and methodsare used to treat one or more volumes of corneal stromal material withtreatment patterns that extend retinal IDM into one or more functionalregions of the retina. Several applications of the device and methodsdescribed in the above-referenced patents are also incorporated hereinfor devices and methods described herein in their entirety by reference.These applications include, but are not limited to, vision and visualfunction improvements, compensation for age-related focus dysfunction,reduction of myopia progression and reduction of axial length elongationprogression.

One highly preferred embodiment of a retinal IDM device and methodproduced the treatment pattern of corneal radii of curvature (ROC) shownin FIG. 11A and the enlarged portion of FIG. 11A shown in FIG. 11B. FIG.11B shows 0.1 mm incremental boundaries in radii of curvature; theactual ROCs vary continuously from one incremental boundary to another.FIG. 12 shows a continuous ROC profile that approximates the ROC profilealong the 30°-210° meridian of the treatment pattern shown in FIG. 11A.The ROCs can be symmetric as shown in FIG. 12 or asymmetric withvariable shapes. Locations of minimum ROCs can be centered or decenteredwith respect to the pupil centroid (or another centration reference).The untreated cornea had a ROC of approximately 7.6 mm in the centraloptical zone (within 3 mm diameter); the treated cornea had ROCs in therange of 7.2 to 7.8 mm within the same zone. The CPV-IDM treatment alsoproduced significant ROC changes throughout the cornea, extending to theperipheral cornea at the 7 mm optical zone. The resultant CPV-IDMtreatment change in FIG. 11A can be approximately described as four setsof alternating steeper/flatter sectors within the central (3 mmdiameter) optical zone surrounded by four sets of flatter regions in theparacentral cornea between ca. 5 to 7 mm optical zone. The variations inROCs produce redirection of light rays from four aspheric extended“lenslets” that redirect retinal irradiance onto functional retinalareas similar to those illustrated in FIG. 9 , as well as redirection oflight rays from other regions of the cornea. The ROC pattern shown inFIGS. 11A and 11B was produced by a retinal IDM device that causedCPV-IDM treatment of four small volumes of corneal stromal tissuelocated underneath the surface treatment areas shown as small whitecircles on FIG. 11A. Due to the biomechanical properties of the cornea,the highly localized treatments in four small volumes of corneal stromaltissue produced non-local effects that extended from each treated volumetoward the corneal center with peak effects approximately midway betweenthe treated volumes and the corneal center. CPV-IDM treatment producednon-local ROC changes over the entire cornea extending from the centerof the cornea to at least the 7 mm optical zone.

In some preferred embodiments of the retinal IDM invention describedherein, devices that use corneal photovitrification (CPV) for retinalIDM produce corneal modifications including, but not limited to,modifications of corneal radii of curvature, corneal indices ofrefraction, corneal diffraction, corneal scattering and any combinationof corneal modifications thereof throughout the cornea using variouspatterns, including but not limited to four circular non-central volumetreatments. In corneal radii of curvature modifications, CPV-IDMtreatment induces various non-central locations and amplitudes of majordepressions and/or elevations in the corneal anterior surface withresultant increases and/or decreases in anterior corneal radii ofcurvature throughout the cornea.

In some preferred embodiments of the invention described herein, CPV-IDMfor retinal IDM produces changes in radii of curvature that alter theirradiance distribution in all four quadrants of the retina, whereinretinal IDM causes decreased or increased irradiance and/or contrast onretinal regions and/or microregions, wherein the changed ratios of lightand dark edges of viewed objects change the irradiance contrast. In someembodiments, CPV-IDM patterns for retinal IDM of the present inventionare centered on the pupil centroid (PC) or corneal vertex (CV) orcoaxially sighted corneal light reflex (CSCLR). In some embodiments,CPV-IDM patterns for retinal IDM are decentered relative to the PC, CVor CSCLR.

In some preferred embodiments of the invention described herein, CPV-IDMfor retinal IDM does not produce deleterious retinal effects including,but not limited to, retinal inflammation and retinal wound healing. Incontrast to conventional devices and methods of retinal laser therapy(including, but not limited to, laser retinal photocoagulation, laserretinal photodynamic therapy and subthreshold micropulse diode lasertherapy) and photobiomodulation therapy, CPV-IDM devices and methods donot use laser or light emitting diode (LED) light to irradiate theretina; CPV-IDM uses only natural environmental light to irradiate theretina and therefore is free from deleterious retinal effects associatedwith exposure of the retina to laser and other unnaturalnon-environmental light. In some preferred embodiments of CPV-IDMtreatments for retinal IDM, only “eyesafe” light is used to irradiatethe cornea; “eyesafe” light is completely absorbed by the cornea andother pre-retinal ocular structures, thereby preventing directirradiation of the retina.

In some embodiments of the retinal IDM invention described herein, theCPV-IDM treatment for retinal IDM of the present invention continues tocompensate for ongoing damage to or decreased functioning of retinalcells from the underlying disease process for months and years after thetreatment of the present invention. In some embodiments, the ongoingneural compensation for ongoing damage to retinal cells or decreasedfunctioning of retinal cells from the underlying disease process isfacilitated by ongoing changes in the retinal IDM produced by methods ofthe present invention, which, for example, enable changes in cornealanterior surface depressions and/or elevations over days, weeks, months,or years. Some preferred embodiments of the invention, such as with somemethods using corneal photovitrification to produce retinal IDM, produceincreases and/or decreases in radii of curvature of the anterior corneathroughout the cornea, that change gradually over days, weeks, months,or years to continue to compensate for ongoing damage to or decreasedfunctioning of retinal cells.

In some embodiments of the retinal IDM invention described herein, theamplitudes of the corneal ROC changes from CPV-IDM treatment diminishover time. In some embodiments of the retinal IDM invention describedherein, the CPV-IDM treatment can be modified by changing the treatmentpattern and/or treatment energy density delivered to the cornea in orderto make the CPV-IDM changes of corneal ROC temporary for differentperiods of time. Temporary CPV-IDM-induced ROC changes are particularlyuseful for treatment of amblyopia in children, adolescents and youngadults. CPV-IDM treatment of both eyes of a subject with amblyopia canprevent vision impairment produced by conventional amblyopia treatmentwith monocular deprivation. CPV-IDM treatment of both eyes of a subjectwith amblyopia can improve binocularity during normal daily functions,in contrast to conventional single eye methods. Binocularity is impededby monocular deprivation treatment for amblyopia and is not improvedduring normal daily functions when conventional binocular visualtraining is performed with or without video games. CPV-IDM treatment ofboth eyes of a subject does not prevent use of both eyes' peripheralvision. The peripheral vision of a subject with amblyopia usually isnormal, can be impaired by occlusion therapy, and can contribute toimprovements in central vision in the amblyopic eye after CPV-IDMtreatment.

In an application of the highly preferred embodiment of the retinal IDMdevice, CPV-IDM treatments on eyes with age-related macular degeneration(AMD) using a treatment pattern similar to that of FIG. 11A producedsignificant retinal IDM vision improvements in mean best-spectaclecorrected distance and near visual acuities (CDVA and CNVA), in contrastsensitivity and other visual functions, and in vision-related quality oflife. FIG. 13 shows an ETDRS visual acuity chart that is used to measurevisual acuity. Distance and near versions of the ETDRS chart areavailable to measure distance and near visual acuities, respectively.ETDRS measurements are reported in several ways: in terms of Snellenvalues, logMAR values, decimal values and/or the number of letterscorrectly read (starting with 0 letters for a Snellen value of 20/1000).Improvements in visual acuity are often reported in terms of lettersgained and/or lines gained on the ETDRS chart; there are 5 letters perline on the chart.

In one case study, Patient A (a female patient 82 years old with dry AMDin both eyes) received CPV-IDM treatments—initially in her left eye (OS)and, 7.2 months later, in her right eye (OD). FIGS. 14 and 15 showPatient A measured CDVA and CNVA values, respectively, as a function oftime. Before treatment of OS, Patient A's best spectacle-correcteddistance visual acuities (CDVAs) were 20/182 (OD) and 20/200 (OS),respectively, and her best spectacle-corrected near visual acuities(CNVAs) were 20/200 (both OD and OS), all in Snellen notation. FIG. 14shows that at 1 day (1 d) after CPV-IDM treatment, Patient A CDVAs were20/138 (OD) and 20/30 (OS), representing 1.2 lines (6 letters) and 8.2lines (41 letters) gain, respectively, on an ETDRS distance visualacuity chart. FIG. 15 shows that at 1 day (1 d) after CPV-IDM treatment,Patient A CNVAs were 20/80 (OD) and 20/50 (OS), representing 4.0 lines(20 letters) and 6.0 lines (30 letters) gain, respectively, on an ETDRSnear visual acuity chart. For Patient A, both CDVA and CNVA continued toimprove further at most CPV post-treatment times extending to 33 months(33 m) for OS and 24 m for OD. These gains are significantly superior tothose obtained by conventional devices and methods used to treat AMDeyes. A conventional implantable miniature telescope (IMT) study in acontrolled clinical trial for similar AMD patients yielded a mean CDVAgain of only 16 letters at 24 m after implantation. In real-life (ascontrasted with controlled clinical trial conditions), conventionaldevices and methods yield even poorer CDVA and CNVA outcomes.

Application of the highly preferred embodiment of the retinal IDM devicealso yielded significantly better outcomes than conventional devices andmethods for many other safety and efficacy measures including, but notlimited to, serious adverse events, vision-related quality of life(VRQoL) and visual functions including, but not limited to, contrastsensitivity. With respect to safety, CPV-IDM treatment has not caused todate any CPV-IDM-related adverse event or complication in patients withdry AMD eyes, in contrast to IMT that has substantial percentages ofserious adverse events. With respect to VRQoL, FIG. 16 shows the VisualFunction Questionnaire-25 (VFQ-25) composite score vs. time for PatientA. The composite score in FIG. 16 is an average of 24 scores (each on a100-point scale; one score for general health is usually omitted) forresponses to items on the VFQ-25 test. Patient A experienced a verylarge increase in vision-related quality life due to CPV-IDM treatment,as measured by the VFQ-25 composite score. Patient A also experiencedvery large increases in component vision scores (for near, distance andperipheral vision) shown in FIG. 17 and in component psychosocial scores(for social functioning, mental health and dependency) shown in FIG. 18. With respect to contrast sensitivity (CS), Patient A also experienceda very large increase in CS, as measured on a Pelli-Robson CS chart,from 0.6 log units pre-CPV-IDM treatment to 1.05 log units (for OD, OSand binocular) at 33 months post-CPV-IDM treatment; this log increaserepresents an increase to 2.8× the pre-treatment value.

Application of the highly preferred embodiment of the retinal IDM devicealso produced a very significant retinal sensitivity improvement forPatient A. FIG. 19 shows a graph of Patient A outcomes of retinalsensitivity measured in microperimeter examinations as a function oftime from pre-CPV-IDM treatment through 24 m post-treatment of OS, theinitially treated eye. Retinal sensitivity is graphed as the percentageof stimulus points in the microperimeter grid (of 37 points distributedover a 10° diameter region centered on the fovea) that have retinalsensitivity ≥5 decibels (dB). For OS, the initial treated eye, thenumber of stimulus points with retinal sensitivity ≥5 dB increased from21 (57%) pre-CPV-IDM treatment to a maximum of 34 (92%) at 18 mpost-treatment and a final value of 31 (84%) at 24 m. Similarly, for OD,the eye treated at 7.2 months after OS treatment, the number of stimuluspoints with retinal sensitivity ≥5 dB increased from 25 (68%)pre-CPV-IDM treatment to a maximum of 34 (92%) at 9 m post-treatment(with respect to the original OS treatment date) and a final value of 32(86%) at 24 m (also with respect to the original OS treatment date). Asthe microperimeter grid of 37 stimulus points is registered on the samepoints throughout measurements at each time, the increase of retinalsensitivity indicates that CPV-IDM-treatment has provided restorativebenefits (i.e., converting some partly or fully dysfunctional regions ofthe retina into partly or fully functional regions.) Therefore, CPV-IDMtreatment may provide a partial cure of AMD in some cases by restorativemechanisms including, but not limited to, beneficial modulation ofretinal trophic factors and retinal regeneration of functional retinalcells.

In another case study, Patient B (a male patient 73 years old with wetAMD in both eyes who is receiving intravitreal injections of anti-VEGFdrugs to reduce progression of vision loss) received CPV-IDM treatmentsin both eyes during a single treatment session. FIGS. 20 and 21 showPatient B measured CDVA and CNVA values, respectively, as a function oftime. Before treatment, Patient B's best spectacle-corrected distancevisual acuities (CDVAs) were 20/160 (OD) and 20/241 (OS), respectively,and his best spectacle-corrected near visual acuities (CNVAs) were20/138 (OD) and 20/152 (OS), all in Snellen notation. FIG. 20 shows thatat 1 day (1 d) after CPV-IDM treatment, Patient B CDVAs were 20/160 (OD)and 20/174 (OS), representing 0 lines (0 letters) and 1.4 lines (7letters) gain, respectively, on an ETDRS distance visual acuity chart.At 1 month after CPV-IDM treatment, Patient B CDVAs were 20/96 OU,representing 2.2 lines (11 letters) and 4.0 lines (20 letters) gain,respectively. FIG. 21 shows that at 1 day (1 d) after CPV-IDM treatment,Patient B CNVAs were 20/83 (both OD and OS), representing 2.2 lines (11letters) and 2.6 lines (13 letters) gain, respectively, on an ETDRS nearvisual acuity chart. At 1 month after CPV-IDM treatment, Patient B CNVAswere 20/63 OU, representing 3.4 lines (17 letters) and 3.8 lines (19letters) gain, respectively. For Patient B, both CDVA and CNVA continuedto improve further extending to 12 months (12 m) post-treatment, withfinal gains of 4.2 lines (21 letters) or more for all visual acuitymeasurements. These gains are significantly superior to those obtainedby conventional devices and methods used to treat wet AMD eyes. Aconventional anti-VEGF injection study in a controlled clinical trialfor wet AMD patients yielded a mean CDVA gain of only 7 letters at 12 mafter starting monthly injections of an anti-VEGF drug. In real-life (ascontrasted with controlled clinical trial conditions), conventionaldevices and methods yield even poorer CDVA and CNVA outcomes.

Application of the highly preferred embodiment of the retinal IDM devicealso yielded significantly better outcomes than conventional devices andmethods for many other safety and efficacy measures including, but notlimited to, serious adverse events, vision-related quality of life(VRQoL) and visual functions including, but not limited to, contrastsensitivity. With respect to safety, CPV-IDM treatments of patients withwet AMD eyes have not caused any CPV-IMD-related adverse event orcomplication, in contrast to intravitreal injection anti-VEGF therapiesthat have substantial percentages of serious adverse events. Withrespect to VRQoL, FIG. 22 shows the Visual Function Questionnaire-25(VFQ-25) composite score vs. time for Patient B. The composite score inFIG. 22 is an average of 24 scores (each on a 100-point scale; one scorefor general health is usually omitted) for responses to items on theVFQ-25 test. Patient B experienced a very large increase invision-related quality life due to CPV-IDM treatment, as measured by theVFQ-25 composite score. Patient B also experienced very large increasesin component vision scores (for near, distance and peripheral vision)shown in FIG. 23 and in component psychosocial scores (for socialfunctioning, mental health and dependency) shown in FIG. 24 . Withrespect to contrast sensitivity (CS), Patient B also experienced a verylarge increase in CS, as measured on a Pelli-Robson CS chart, from 1.05log units pre-CPV-IDM treatment to 1.35 log units (for OD, OS andbinocular) at 12 months post-CPV-IDM treatment; this log increaserepresents an increase to 2× the pre-treatment value.

Patient B was diagnosed with wet AMD in both eyes during 2014 and hasbeen receiving anti-VEGF intravitreal injections since then atrelatively high frequency—for the 12 months before CPV-IDM treatment, 8injections OD and 6 injections OS and for the 10 months after CPV-IDMtreatment, 8 injections in each eye. Patient B is a combination therapycase in which anti-VEGF injections were, and are continuing to be, usedto reduce the neovascularization associated with wet AMD and CPV-IDMtreatment was used to improve vision. In some embodiments of theinventions presented herein, combination therapy (involving IDM therapyincluding, but not limited to CPV-IDM treatment plus another therapyincluding, but not limited to, pharmacological therapy) producessuperior outcomes compared to monotherapy (including, but not limitedto, pharmacological therapy).

It can be appreciated by anyone skilled in the art that individualcustomized retinal IDM treatments can be performed by CPV-IDM forretinal IDM and other devices and methods of the invention describedherein. These individual customized retinal IDM treatments can be basedon diagnostic information including, but not limited to, individualoptical coherence tomography, microperimetry, high definition perimetryand fundus autofluorescence examinations.

In some embodiments of the invention described herein, retinal IDMtreatment patterns can be configured based on the extent of maculardamage and visual field loss in order to improve vision of patients withglaucoma. Glaucomatous damage to the macula occurs early in the diseaseprocess and is more common in the upper visual field where local anddeep arcuate defects can appear near fixation. Early glaucomatous damageproduces significant reduction in binocular contrast sensitivity scoresand depth perception which may be improved by bilateral retinal IDM.

FIG. 25 shows unmodified and modified retinal irradiance distributionswith a schematic illustration of the effect of a central dysfunctionalretinal area (shaded gray). In the unmodified retinal irradiancedistribution (top graph), only a small portion (4.3%) of the lightirradiates the functional retinal area that is outside the dysfunctionalretinal area. Conventional modification by 2× magnification such as isproduced by IMT implantation (bottom left graph) increases the usefulretinal irradiance to 30% that is outside the dysfunctional retinal areaand inside the functional retinal area. Optimized modification using theinvention described herein (bottom right graph) produces retinal IDMsimilar to that shown in FIG. 7 , increasing the useful retinalirradiance to 83% that is outside the dysfunctional retinal area andthus inside the functional retinal area. Conventional modification bymagnification, the basis of IMT and similar intraocular telescopedevices, is always limited in effectiveness to improve vision for eyeswith central vision loss. In addition, the IMT device causes “tunnelvision” due to the restricted field of view of the telescope optics.Corneal treatment by a CPV-IDM device, the preferred embodiment of theinvention described herein, is much more effective in improving visionfor eyes with central vision loss and also improves peripheral visionrather than causing “tunnel vision”.

Some embodiments of the retinal IDM invention described herein involvenon-CPV-IDM devices and methods that are configured to produce cornealmodifications including, but not limited to, modifications of cornealradii of curvature, corneal indices of refraction, corneal diffraction,corneal scattering and any combination of corneal modifications thereoffor light redirections away from the fovea or another retinal fixationregion to at least two other retinal regions for retinal IDM. Theseembodiments include, but are not limited to, corneal devices and methodsfor corneal photodisruption, corneal photoionization, cornealdissociation, corneal photoablation, photothermal keratoplasty (LTK),corneal photowelding, corneal crosslinking (CXL), conductivekeratoplasty (CK), and corneal inlays, all of which are configured forretinal IDM. For optimal retinal IDM, the changes of radii of curvatureand/or refractive indices should produce as much retinal IDM as possibleoutside of dysfunctional retinal areas and inside functional retinalareas. Non-CPV-IDM treatment devices and methods can be configured toproduce corneal radii of curvature (ROC) changes including, but notlimited to those shown in FIGS. 11 and 12 , for corneal anterior surfaceROC changes for retinal IDM. IDM treatment and devices can be configuredto produce lenticular radii of curvature or indices of refractionmodifications of the natural crystalline lens for retinal IDM usingdevices, including, but not limited, to a femtosecond laser forphotodisruption. It is understood that corneal modifications can be madeinitially (the first modification) and at later times (the subsequentmodifications).

In some embodiments of the retinal IDM invention described herein,femtosecond (FS) lasers or nanosecond leasers can be used to produceintrastromal photodisruptions or photoionizations or photodissociationsor any combination thereof for retinal IDM by means of cornealmodifications. FIG. 26 illustrates a schematic cross-section through acornea that has received a femtosecond (FS) laser treatment (Tx) patternconfigured to produce retinal IDM. In the example shown, intrastromal FSlaser irradiations are configured to remove intrastromal corneal volumesthat lead to depressions (exaggerated in depth in FIG. 26 ) and, hence,radius of curvature (ROC) changes in the anterior corneal surface; as analternative, FS laser irradiations can be configured to produce othercorneal modifications including, but not limited to, intrastromal indexof refraction modification, intrastromal diffraction modification andintrastromal scattering modification for retinal IDM; any combination ofcorneal modification changes can be used for retinal IDM. FS laserpatterns for corneal tissue removal or changes in index of refractioncan be spherical as shown in FIG. 26 or can have any volumetric shape.FS treated volumes can be located at any depth within the cornealstroma. Two or more FS treated volumes can be generated centrally(within the 3 mm optical zone), paracentrally (within the 3 to 6 mmoptical zone) or peripherally (at >6 mm optical zone), with centrationor decentration of the treatment pattern with respect to the pupilcentroid or another centration reference. The treated volumes can beequal or unequal in shape and/or depth to produce custom effects. UnlikeFS annular intrastromal treatments previously used for otherapplications such as presbyopia correction, the FS laser modificationsof the present invention are not 360 degree annular volumes and,therefore, do not induce corneal ectasia.

In some embodiments of the retinal IDM invention described herein, lasertissue removal procedures including, but not limited to, laserphotodisruption, photoionization or photodissociation and/or laserphotoablation devices and methods [including, but not limited to, SmallIncision Lenticule Extraction (SMILE), Laser In-Situ Keratomileusis(LASIK) and PhotoRefractive Keratectomy (PRK) devices and methods] canbe used to produce corneal modifications that are useful for retinalIDM. FIG. 12 shows a cross-section through a cornea with an anteriorsurface ROC profile that is configured to be useful for retinal IDM.Laser tissue removal procedures (including, but not limited to,femtosecond laser treatment to form a corneal lenticule for SMILEtreatment, and laser photoablation of the stromal bed for LASIKtreatment and for PRK treatment) should be configured to produce cornealmodifications that are sufficient to provide retinal IDM.

In some embodiments of the retinal IDM invention described herein,corneal crosslinking devices, including but not limited to ultraviolet A(UVA) light emitting devices, LTK devices, and CPV devices that can becombined with a photosensitizer, including, but not limited to,riboflavin, or other photoactivation systems with photoactivationagents, including, but not limited to, glyceraldehyde, glutaraldehyde,genipin, nitroalcohols or formaldehyde-releasing agents, for cornealcrosslinking (CXL) procedures are configured to produce focal areas ofcrosslinking (FCXL) In some embodiments of a FCXL IDM procedure, cornealareas that are not to be treated are masked from UVA light or otherlight or photoactivator in two or more spatially separated treatmentareas of the cornea for the application of retinal IDM. FCXL may beperformed with or without removal of the corneal epithelium, in whole orin part, to enhance the penetration of a photosensitizer into thecorneal stroma, including, but not limited to, administration of aphotosensitizer (including, but not limited to, riboflavin) to thecornea followed by UVA or other light irradiation. FXCL can also beproduced by using combined laser thermal keratoplasty plus CXL usingphotosensitizers including, but not limited to, riboflavin that isactivated by high irradiance (10 W/cm² or greater irradiance) visible orUVA light sources including, but not limited to, GaN diode lasers anddiode-pumped solid state (DPSS) lasers operating in the 360 to 460 nmwavelength region. FXCL IDM devices and methods are configured toproduce corneal modifications including, but not limited to, cornealradius of curvature modifications shown in FIGS. 11 and 12 using varioustreatment patterns, including but not limited to two or more non-centraltreatments to induce various locations and amplitudes of cornealmodifications for light redirections away from the fovea to two otherretinal regions. Within each treatment pattern, FCXL is configured toproduce treatment volumes that are at least 0.1 mm in diameter and thatare located paracentrally (within the 3 to 6 mm optical zone) orperipherally (at >6 mm optical zone), with centration or decentration ofthe treatment pattern with respect to the pupil centroid or anothercentration reference.

In some embodiments of the retinal IDM invention described herein,conventional corneal shape changing procedures and devices including,but not limited to, conductive keratoplasty (CK) and devices, includingbut not limited to radiofrequency emitting devices, are configured toproduce corneal modifications in two or more spatially separatedtreatment areas of the cornea for retinal IDM. CK-produced cornealmodifications include, but are not limited to, corneal radius ofcurvature modifications shown in FIGS. 11 and 12 using various treatmentpatterns, including but not limited to two or more non-centraltreatments to induce various locations and amplitudes of ROCmodifications. Within each treatment pattern, CK is configured toproduce treatment volumes that are at least 0.1 mm in diameter and thatare located paracentrally (within the 3 to 6 mm optical zone) orperipherally (at >6 mm optical zone), with centration or decentration ofthe treatment pattern with respect to the pupil centroid or anothercentration reference.

In some embodiments of the invention described herein, retinal IDM isproduced by insertion of an intraocular lens (IOL) and/or an intraocularlens accessory device (IOLAD) configured to modify the retinal IDM.IOLADs include, but are not limited to, light-steering structuresincluding, but not limited to, refractive structures, diffractivestructures or any combination thereof that act in combinations with IOLsto modify the retinal IDM. IOLs and IOLADs for phakic, aphakic orpseudophakic eyes include, but not limited to, IOLs and IOLADspositioned in the sulcus or capsular bag, anterior chambers IOLs andIOLADs, iris-fixated IOLs and IOLADs and transscleral-sutured IOLs andIOLADs. FIG. 27 illustrates an IOL modification suitable for retinal IDMthat includes four paracentral regions with IOL modifications including,but not limited to, modifications of IOL radii of curvature, IOL indicesof refraction, IOL diffraction, IOL scattering and any combination ofIOL modifications thereof compared to the other regions of the IOL. Inthe case of IOL diffraction modifications, the modifications of theinvention described herein are different from annular (ring-likepatterns centered of the IOL center) modifications that are used indiffractive multifocal IOLs; for example, FIG. 27 illustrates fourseparate paracentral regions, one or more of which incorporatemodifications of IOL diffraction. Additional IOL modifications include,but are not limited to, inclusion of light-steering structures(including, but not limited to, one or more reflectors, one or moreoptical fibers, one or more prisms or any combination of light-steeringstructures) within at least one paracentral region of the IOL. It isunderstood that two, three or more central, paracentral or peripheralregions that are spatially separated, with or without overlapping of theregions, can be used to produce IOL modifications in any or all of theregions for light redirections away from the fovea or another retinalfixation region to two or more retinal regions. It is also understoodthat IOL and IOLAD modifications can be configured in the IOL and IOLADbefore and/or after IOL and IOLAD insertion; after insertion, a FSlaser, another light source and/or electronic means can be used toproduce IOL and IOLAD modifications in situ in order to produceadjustments to IOL and IOLAD radii of curvature, IOL and IOLAD indicesof refraction, IOL and IOLAD light-steering structures, IOL and IOLADdiffraction, IOL and IOLAD scattering and any combination of adjustmentsthereof.

FIG. 28 illustrates an IOL modification suitable for retinal IDM thatincludes two or more prisms that direct irradiance onto functional areasof the retina. In addition, IOLs can be configured to include acombination of at least two central, paracentral or peripheral regionsthat are spatially separated, with or without overlapping of the regionsto modify radii of curvature and/or indices in refraction in any or allof the regions and two or more prisms can be used for retinal IDM. Foroptimal retinal IDM in eyes with dysfunctional retinal areas, thechanges of radii of curvature, changes of refractive indices, prismaticeffects, or any combination thereof should produce as much retinal IDMas possible outside of dysfunctional retinal areas and inside functionalretinal areas.

Some embodiments of the retinal IDM invention described herein involveretinal IDM produced by spectacles, contact lenses or any combinationthereof, with modifications including, but not limited to, modificationsof radii of curvature, indices of refraction, diffraction, scatteringand any combination of modifications thereof for light redirection awayfrom the fovea or another retinal fixation region to at least two otherretinal regions that are configured to produce retinal IDM. FIG. 29shows a cross-section of a modified contact lens (CL; dimensions: 8 mmdiameter, 0.2 mm thickness, 7.8 mm anterior and posterior radii ofcurvature) that includes paracentral steepened regions designed toredirect retinal irradiance from dysfunctional to functional retinalareas. CL dimensions may be different from those shown to includesmaller or larger diameters, thicknesses and radii of curvature.Spectacle lenses can also be designed for retinal IDM. Spectacle lenses(SLs) and CLs may be fabricated from a single material or multiplematerials. CLs may be corneal, scleral or a combination thereof.Modified SL and CL regions may have different or the same radii ofcurvature, different or the same refractive indices, different or thesame diffraction, different or the same scattering or any combinationthereof. Additional spectacle modifications include, but are not limitedto, inclusion of light-steering structures including, but not limitedto, at least one reflector and at least one optical fiber array withinone or both spectacle lenses. There may be 1, 2 or more than 2 modifiedregions that are located centrally, paracentrally or peripherally withinthe CL diameter and/or within the SL shape. SLs and CLs may be used inone eye, both eyes or in any SL and CL combination. All SL and CLcharacteristics, dimensions and modifications are designed to directlight rays into an optimal retinal irradiance distribution for patientretinal IDM requirements. SLs and CLs can be configured statically oractively wherein static configuration is completed prior toincorporation within the ocular system and wherein active configurationis accomplished one or more times after incorporation within the opticalsystem by means of adjustments including, but not limited to, electronicand/or photonic adjustments to corneal radii of curvature changes,indices of refraction changes, diffraction changes, scattering changesand any combination of changes thereof.

Some further embodiments of the retinal IDM invention described hereininvolve the use of “trial” spectacle lenses (SLs), “trial” contactlenses (CLs), or any combination thereof for screening and/orcustomization purposes. In the screening application, “trial” lenses mayhelp to determine whether patient eyes are capable of achieving visionand visual function improvements by retinal IDM devices and methods. Inthe customization application, “trial” lenses may be varied incharacteristics to determine the optimal retinal IDM configuration. Inboth the screening and customization applications, it may be desirablefor the patient to use the “trial” lenses for an extended period of daysor weeks in order to obtain neuroadaptation benefits.

Some embodiments of the retinal IDM invention described herein involveretinal IDM produced by corneal inlays (CIs). FIG. 30 shows a cornealinlay (CI) that is implanted into the cornea; the corneal segment shownis ca. 1.8 mm long with a central thickness of 0.55 mm but the cornealsegment can have lengths extending to ca. 11 mm. Two lenses are shown onthe inlay; these lenses can have the same or different modificationsincluding, but not limited to, modifications of radii of curvature,indices of refraction, diffraction, scattering and any combination ofmodifications thereof. CI shapes can be circular or non-circular. The CIdimensions include, but are not limited to, lengths of 1 to 8 mm, widthsof 1 to 8 mm, diameters of 3 to 8 mm and uniform or variable thicknessesin the range of 0.01 to 0.5 mm. There can be one, two, or more inlays,each of which can have 0, 1, 2, or more lenses. The inlay(s) can belocated centrally as shown in FIG. 30 or can be located eccentrically.The inlay(s) can be implanted at depths from the anterior cornealsurface including, but not limited to, depths of 0.05 to 0.5 mm. Thelenses on each corneal inlay can be located on any position on eachinlay. CIs are composed of materials including hydrogels, biocompatiblematerials and other materials known to those skilled in the art. Cornealinlays can be configured statically or actively wherein staticconfiguration is completed prior to implantation within the cornea andwherein active configuration is accomplished one or more times afterimplantation within the cornea by means of adjustments including, butnot limited to, electronic and/or photonic adjustments to corneal radiiof curvature changes, indices of refraction changes, diffractionchanges, scattering changes and any combination of changes thereof.

In some embodiments of the retinal IDM invention described herein,retinal IDM devices and methods combine retinal IDM teachings with priorart retinal treatments, including pharmacological and/or retinal laserand/or radiation and/or stem cell transplantation and/or epigeneticand/or genetic and/or other therapy (hereafter other therapies) in orderto improve treatment of macular degeneration and/or diabetic retinopathyand/or glaucoma and/or other neovascular and/or atrophic and/orinflammatory and/or genetic and/or nutritional and/or age-relatedretinal diseases (hereinafter “retinal diseases”). The devices andmethods of the present invention overcome drawbacks and deficiencies ofprior art by introducing different mechanisms of vision and/or retinalpathology and/or repair processes associated with retinal diseases. Thedevices and methods of the present invention overcome drawbacks anddeficiencies of prior art therapies by synergistically combining themwith retinal IDM with other therapies to improve visual and/or anatomicoutcomes, which also improves patient compliance with prior art therapy.The combination therapy can be administered in the same patient visit orsequentially at different times. In some embodiments of combinationtherapy, retinal IDM treatment is delivered at one time, either beforenon-retinal IDM therapy or at some time following initiation ofnon-retinal IDM therapy. In some embodiments of combination therapy,more than one retinal IDM treatment is delivered at separate times,either before other therapies or at variable times following initiationof non-retinal IDM therapy.

In some embodiments of the retinal IDM invention described herein,retinal IDM treatment is combined with other therapies for retinaldiseases, including but not limited to retinal laser therapies,including but not limited to photobiomodulation, laser photocoagulation,laser photodynamic therapy, subthreshold micropulse laser therapy,glaucoma laser therapy, (including, but not limited to, lasertrabeculoplasty and cyclophotocoagulation), glaucoma filtration surgery(including, but not limited to, trabeculectomy, microtrabeculectomy,internal or external tube shunt implantation, suprachoroidal shuntimplantation), stem cell transplantation, and radiation therapy(including but not limited to focal intraocular strontium 90 betaradiation).

In some embodiments of the retinal IDM devices and methods describedherein, retinal IDM treatment is combined with other therapies forretinal diseases including, but not limited to, genetic, epigenetic andoptogenetic therapy.

In some embodiments of the retinal IDM invention described herein,retinal IDM treatment is combined with pharmacological treatment ofretinal diseases, including pharmacologic agents, including nutritionalsupplements, administered orally, topically to the cornea, viasubconjunctival injection, via intravitreal injection, intraretinally,via implants and via iontophoresis.

In some embodiments of the retinal IDM invention described herein,retinal IDM treatment is combined with antiangiogenesis drug therapy.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of ameliorating or treating an oculardisorder, including but not limited to macular degeneration, choroidalneovascularization or diabetic retinopathy in a subject comprisingtreatment by retinal IDM in combination with administering atherapeutically effective amount of any vascular endothelial growthfactor (VEGF) antagonist including, but not limited to ranibizumab,bevacizumab, brolucizumab and aflibercept, in combination withadministering a therapeutically effective amount of any PDGF antagonistincluding, but not limited to, volociximab and P200, or in combinationwith any combination of the above drugs. As used herein, the term“ameliorating” or “treating” or “compensating for” means that theclinical signs and/or symptoms associated with an ocular disorder (e.g.,macular degeneration) are lessened as result of the actions performed.The signs or symptoms to be monitored will be characteristic of theocular disorder and will be well known to physicians skilled in the art,as will the methods for monitoring the signs, symptoms and conditions.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of ameliorating or treating an oculardisorder, including but not limited to macular degeneration, choroidalneovascularization or diabetic retinopathy in a subject comprisingtreatment by retinal IDM in combination with administration of atherapeutically effective amount of vetalanib or pazopanib or any othertyrosine kinase inhibitor or any other inhibitor of phosphorylation ofVEGF and PDGF receptors.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating an ocular disease in a subjectcomprising treatment by retinal IDM in combination with administering atherapeutically effective amount of an inhibitor of VEGF activity.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease in a subject comprising treatment by retinal IDM in combinationwith administering a therapeutically effective amount of an inhibitor ofalpha5beta1 integrin activity.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to a neovascular ocular diseaseand/or wet macular degeneration, and/or diabetic retinopathy, in asubject comprising treatment by retinal IDM in combination withadministering a therapeutically effective amount of an inhibitor of PDGFactivity.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to a neovascular ocular diseaseand/or wet macular degeneration, and/or diabetic retinopathy, in asubject comprising treatment by retinal IDM in combination withadministering a therapeutically effective amount of an inhibitor oftyrosine kinase activity.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to a neovascular ocular diseaseand/or wet macular degeneration, and/or diabetic retinopathy, in asubject comprising treatment by retinal IDM in combination withadministering a therapeutically effective amount of an inhibitor of mTOR(sirolimus).

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to a neovascular ocular diseaseand/or wet macular degeneration, and/or diabetic retinopathy, in asubject comprising treatment by retinal IDM in combination withadministering a therapeutically effective amount of fluocinoloneacetonide or any other anti-inflammatory agent, wherein theanti-inflammatory agent is delivered by intravitreal injection ordelivered by an intraocular implant.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to geographic atrophy and/or drymacular degeneration, in a subject comprising treatment by retinal IDMin combination with administrating a therapeutically effective amount ofan inhibitor of complement, including but not limited to complement 3 or5, activity.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to geographic atrophy and/or drymacular degeneration in a subject comprising treatment by retinal IDM incombination with administering a therapeutically effective amount ofavacincaptad pegol, LEG316, POT-4, eculizumab, JPE-1375, ARC1905 or anyother complement inhibitor.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to geographic atrophy and/or drymacular degeneration in a subject comprising treatment by retinal IDM incombination with administering a therapeutically effective amount ofdoxycycline.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to geographic atrophy and/or drymacular degeneration in a subject comprising treatment by retinal IDM incombination with administering a therapeutically effective amount ofglatiramer acetate or other T helper 2 inducer or immunomodulator.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to geographic atrophy and/or drymacular degeneration in a subject comprising treatment by retinal IDM incombination with administering a therapeutically effective amount ofOT551, or any other downregulator of overexpression of the proteincomplex nuclear factor (NF)¬B or any other antioxidant, or combinationof antioxidants, including but not limited to combinations of vitamin C,vitamin E, beta-carotene or lutein and zeaxanthin, and omega-3 fattyacids as in for, example, the Age-Related Eye Disease Study (AREDS) andAREDS 2 studies.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to geographic atrophy and/or drymacular degeneration in a subject comprising treatment by retinal IDM incombination with administering a therapeutically effective amountnicotinamide adenine dinucleotide (NAD) or any precursors of NAD,including but not limited nicotinamide riboside or nicotinamidemononucleotide.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to geographic atrophy and/or drymacular degeneration in a subject comprising treatment by retinal IDM incombination with administering a therapeutically effective amount of atrophic factor including, but not limited to, pigment epithelium-derivedfactor (PEDF), fibroblast growth factors (FGFs) and lensepithelium-derived growth factor (LEDGF).

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to geographic atrophy and/or drymacular degeneration in a subject comprising treatment by retinal IDM incombination with administering a therapeutically effective amount ofciliary neurotrophic factor (CNTF) or any other neurotrophic factors orany other inhibitors of photoreceptor apoptosis.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to geographic atrophy and/or drymacular degeneration in a subject comprising treatment by retinal IDM incombination with administering a therapeutically effective amount of aneuroprotective agent, including but not limited to brimodinine.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to geographic atrophy and/or drymacular degeneration in a subject comprising treatment by retinal IDM incombination with administering a therapeutically effective amount of aFas inhibitor or other agent designed to protect retinal cells from celldeath.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to geographic atrophy and/or drymacular degeneration and/or neovascular macular degeneration and/orglaucoma in a subject comprising treatment by retinal IDM in combinationwith administering a therapeutically effective amount of a statin,including but not limited to atorvastin, lovastation, rosuvastatin,fluvastatin or simvastatin.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to glaucoma or ocular hypertension ina subject comprising treatment by retinal IDM in combination withadministering a therapeutically effective amount of an intraocularpressure (IOP)—lowering agent, including but not limited to a miotic, analpha or alpha/beta adrenergic agonist, a beta-blocker, a Ca2+ channelblocker, a carbonic anhydrase inhibitor, chlolinesterase inhibitor, aprostaglandin agonist, a prostaglandin, a prostamide, a cannabinoid, andcombinations thereof.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to glaucoma in a subject comprisingtreatment by retinal IDM in combination with administering atherapeutically effective amount of a pharmacological agent decreasingretinal ganglion cell dysfunction and/or pathology, related to ischemiaor excitotoxicity.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to glaucoma in a subject comprisingtreatment by retinal IDM in combination with administering atherapeutically effective amount of a pharmacological agent decreasingexcessive excitatory amino acid (EAA) stimulation (EAA permits thebipolar and amacrine cells to communicate with the ganglion cell),including but not limited to a glutamate antagonist and/or anycombination of a glutamate antagonist and at least one IOL-loweringagent.

In some embodiments of the retinal IDM invention described herein,retinal IDM provides a method of treating or ameliorating an oculardisease, including but not limited to glaucoma in a subject comprisingtreatment by retinal IDM in combination with administering atherapeutically effective amount of a pharmacological agent providingneuroprotection and/or neuroregeneration of retinal ganglion cells,including but not limited to a rho-kinase (ROCK) inhibitor or anadenosine receptor agonist.

What is claimed:
 1. An apparatus for improving or restoring vision of aneye having a preferred retinal locus of fixation, the apparatuscomprising one or more components configured to be positioned anteriorto a retina of the eye and to redirect environmental light within anocular field of view away from the preferred retinal locus of fixationof the eye to a plurality of retinal locations that are not thepreferred retinal locus of fixation, and the apparatus not producingcorneal vitrification.
 2. The apparatus of claim 1, further comprising acomponent configured to determine the preferred retinal locus offixation of the eye.
 3. The apparatus of claim 1, further comprising atleast one of a refractive component or a diffractive component.
 4. Theapparatus of claim 1, wherein the apparatus is configured to modify morethan one radius of curvature of at least one of the apparatus or astructure within the eye.
 5. The apparatus of claim 1, wherein theapparatus is configured to modify more than one index of refraction ofat least one of a component of the apparatus or a structure within theeye.
 6. The apparatus of claim 1, wherein the apparatus is configured tomodify diffraction within at least one of a component of the apparatusor a structure within the eye.
 7. The apparatus of claim 1, wherein theplurality of retinal locations to which the environmental light isredirected are disposed within genetically altered portions of theretina.
 8. The apparatus of claim 1, wherein the plurality of retinallocations to which the environmental light is redirected are disposedwithin epigenetically altered portions of the retina.
 9. The apparatusof claim 1, wherein the plurality of retinal locations to which theenvironmental light is redirected are disposed withinneuroregeneratively altered portions of the retina.
 10. The apparatus ofclaim 1, wherein the plurality of retinal locations to which theenvironmental light is redirected are disposed within portions of theretina that includes at least one of a retinal transplant, an implantedretinal cell, an implanted stem cell, or an implanted prosthesis. 11.The apparatus of claim 1, wherein: the apparatus comprises a lens, thelens configured to be positioned in front of or on the eye and havingtwo or more noncentral, non-annular, and separate modified portions, thetwo or more noncentral, non-annular, and separate modified portionsconfigured for directing laser light or non-laser ultraviolet light tomodify a structure within the eye, the modified structure configured forredirecting environmental light within the ocular field of view awayfrom the preferred retinal locus of fixation of the eye to the pluralityof retinal locations that are not the preferred retinal locus offixation, and the apparatus not producing corneal vitrification; and afirst value of a radius of curvature or an index of refraction of eachof the two or more noncentral, non-annular, and separate modifiedportions of the lens differs from a second value of the radius ofcurvature or the index of refraction characterizing at least oneadditional portion of the lens.
 12. An apparatus for improving orrestoring vision of an eye having a preferred retinal locus of fixation,the apparatus comprising a lens, the lens configured to be positioned infront of or on the eye and having two or more noncentral, non-annular,and separate modified portions, the two or more noncentral, non-annular,and separate modified portions configured for directing laser light ornon-laser ultraviolet light to modify a structure within the eye, themodified structure configured for redirecting environmental light withinthe ocular field of view away from the preferred retinal locus offixation to a plurality of retinal locations that are not the preferredretinal locus of fixation, and the apparatus not producing cornealvitrification, wherein a first value of a radius of curvature or anindex of refraction of each of the two or more noncentral, non-annular,and separate modified portions of the lens differs from a second valueof the radius of curvature or the index of refraction characterizing atleast one additional portion of the lens.